Fungicides have myriad uses, including for crop protection; as food, feed, and cosmetics preservatives; and as pharmaceuticals for both human and veterinary applications. Crop yield reduction, food-borne diseases and fungal infections of both humans and animals are a problem in both developed and developing countries. Therefore, improvements to the efficacy of existing fungicides, especially those that are environmentally friendly and are not susceptible to development of fungal resistance are highly desirable.
Polyene fungicides are antifungal antibiotics that have been used in all of the aforementioned fields. They may be obtained through fermentation of Streptomyces species, such as Streptomyces natalensis, which is commonly found in soil. Activity of polyene fungicides derives, in part, from their ability to damage cell membranes by forming complexes with ergosterol. Numerous studies have confirmed that the potential for development of fungi resistant to natamycin is very low. Further, polyene fungicides have negligible toxicity, as they do not affect the cholesterol present in mammalian cells.
Non-ribosomal peptides, including cyclic amphiphilic lipopeptides such as surfactins, iturins and fengycins, are well-recognized for their antimicrobial properties and have been used in the field of crop protection. Because of their mode of action, they also have potential uses in biopharmaceutical and other biotechnology applications. Lipopeptides may be obtained through fermentation of various soil bacteria, including Bacillus subtilis and Bacillus amyloliquefaciens. Lipopeptides, similarly to polyene fungicides, kill fungi by disrupting cell membranes. The potential for the development of fungal resistance to these compounds is expected to be very low since they act directly upon membrane lipids and not on a single site protein target. Further, lipopeptides are environmentally friendly and of low risk to workers and consumers; in fact, crops treated with lipopeptide-containing Bacillus strains may be harvested on the day of treatment. Applicants have discovered that combinations of polyene fungicides and lipopeptides cause a synergistic, rather than simply an additive, increase in efficacy against microorganisms such as fungi. Without wishing to be bound by any theory, Applicants hypothesize that the lipopeptides and polyene fungicides of the present invention act in a synergistic fungicidal manner because each type of compound disrupts fungal cell membranes via a distinct mode of action.